EP1978807B1 - Method of treating chronic kidney disease - Google Patents

Method of treating chronic kidney disease Download PDF

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EP1978807B1
EP1978807B1 EP07717051.2A EP07717051A EP1978807B1 EP 1978807 B1 EP1978807 B1 EP 1978807B1 EP 07717051 A EP07717051 A EP 07717051A EP 1978807 B1 EP1978807 B1 EP 1978807B1
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ferric citrate
ferric
precipitate
kidney disease
chronic kidney
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French (fr)
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EP1978807A4 (en
EP1978807A2 (en
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Keith Chan
Winston Town
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Panion and BF Biotech Inc
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Panion and BF Biotech Inc
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Priority claimed from PCT/US2006/032385 external-priority patent/WO2007022435A2/en
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Priority to EP16161784.0A priority Critical patent/EP3066923A3/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/295—Iron group metal compounds
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
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    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
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    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P27/00—Drugs for disorders of the senses
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    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A—HUMAN NECESSITIES
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    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
    • A—HUMAN NECESSITIES
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part

Definitions

  • This invention relates to the uses of pharmaceutical-grade ferric citrate compounds for use in a method of preventing, reversing, maintaining, delaying progression of chronic kidney disease.
  • Chronic kidney disease is a gradual and progressive loss of the ability of the kidneys to excrete wastes, concentrate urine, and conserve electrolytes. Unlike acute kidney failure with its abrupt but reversible of kidney function, the kidney functions in chronic kidney disease progress and deteriorate irreversibly towards end stage renal disease (ESRD). Patients suffering from ESRD cannot survive without dialysis or kidney transplantation.
  • ESRD end stage renal disease
  • the U.S. National Kidney Foundation defines chronic kidney disease according to the presence or absence of kidney damage and the level of kidney function, regardless of the type (clinical diagnosis) of kidney disease.
  • the primary measure of kidney function is glomerular filtration rate (GFR), which is often estimated as creatinine clearance from serum and urine creatinine concentrations.
  • GFR glomerular filtration rate
  • Chronic kidney disease or failure is defined as having glomerular filtration rate less than 60 ml/min for three months or more.
  • Progression of chronic kidney disease occurs from chronic tubulointerstitial inflammation caused by increases in single nephron filtered load of phosphate, absolute tubular re-absorption of phosphate, calcium phosphate product in the tubular lumen and by precipitation of calcium phosphate in the tubules and interstitium, which is facilitated by reduced concentration of citrate in the tubular fluid (precipitation-calcification hypothesis).
  • Hyperparathyroidism is one of the earliest manifestations of impaired renal function, and minor changes in bone have been found in patients with a glomerular filtration rate of 60 ml/min (chronic kidney disease stage 2 to 3). With the worsening of kidney condition and phosphorus accumulation, parathyroid will continuously increase the release of parathyroid hormone (PTH) and lead to the development of hyperparathyroidism. High PTH will increase calcium release from bone to serum. The result is abnormal serum concentrations of calcium and phosphorus and lead to bone disease and extraskeletal calcification. Precipitation of calcium phosphate in renal tissue begins early. This may influence the rate of progression of renal disease, and is closely related to hyperphosphatemia and calcium phosphate (CaxP) product.
  • PTH parathyroid hormone
  • CaxP calcium phosphate
  • Acid-base balance is normally maintained by renal excretion of the daily acid load. As renal function declines, the acid-base balance is maintained by various compensatory mechanisms, of which an increase in the synthesis of ammonia by proximal tubule is the most important. A defective trapping of ammonia in the medulla poses further demands on proximal tubules to increase synthesis of ammonia and results in an enhanced concentration of ammonia in renal cortex. High concentration of free-base ammonia in renal cortex can result in complement activation and interstitial inflammation which has been reported to be one of the major determinant of progressive renal injury. Renal acidosis result in bone demineralization, hyperparathyroidism, increase protein catabolism, insulin resistance and stunted growth. Recent observations suggest that acidosis triggers inflammation and accelerates progression of chronic kidney disease.
  • kidney stone could cause urine obstruction, urinary tract infection and may result in development of chronic kidney disease.
  • NaHCO3 is used to ameliorate one of the uremic syndromes such as metabolic acidosis which leads to osteopenia and urinary calcium excretion.
  • Ferric iron containing compounds are useful in the treatment of a number of disorders, including hyperphosphatemia and metabolic acidosis. See Hsu et al., New Phosphate Binding Agents: Ferric Compounds, J Am Soc Nephrol. 10:1274-1280 (1999 ). Previous studies and inventions have reported the use of ferric compounds in binding dietary phosphates, and such ferric compounds are potentially useful for the treatment of hyperphosphatemia in renal failure patients ( U.S. Patent No. 5,753,706 ; U.S. Patent No. 6,903,235 ; CN 1315174 ; Yang et al., Nephrol. Dial. Transplant 17:265-270 (2002 )).
  • Elevated amounts of phosphate in the blood can be removed by administering compounds such as ferric citrate. Once in solution, the ferric iron binds phosphate, and the ferric phosphate compounds precipitate in the gastrointestinal tract, resulting in effective removal of dietary phosphate from the body. It is also believed that the absorbed citrate from ferric citrate is converted to bicarbonate which corrects metabolic acidosis, a condition common in renal failure patients.
  • U.S. Patent No. 5,753,706 discloses the use of ferric containing compounds, including ferric citrate and ferric acetate in the crystalline form, in an orally effective 1 gram dosage form to bind to soluble dietary phosphate, thus causing precipitation of phosphate as ferric or ferrous phosphates in the gastrointestinal tract and preventing oral absorption of soluble phosphates from dietary sources. Since binding of ferric ions to soluble phosphate in the gastrointestinal tract would require dissolution of the orally administered ferric citrate, and since the rate of dissolution of crystalline ferric citrate is slow (over 10-12 hours at 37°C), oral administration of a substantially large dose of 1 g of ferric citrate is required.
  • a related Chinese patent application ( CN 1315174 ) also discloses a similar use of ferric citrate and related compounds in an oral solution dosage form for the treatment of hyperphosphatemia in renal failure patients.
  • Fe (III) is a Lewis acid and is chemically less soluble in the stomach at pH below 5 than at intestinal pH normally above 7.
  • the stomach is, however, believed to be an important site of action for the dissolution of Fe (III) compounds. It is believed that the stomach is an important site of action for Fe (III) to mediate its action in binding to dietary phosphates, preventing phosphate from reaching the intestine and thus reducing absorption of phosphates from the intestine.
  • the present invention discloses these novel forms of ferric organic compounds possess several characteristics beneficial for the treatment or modification of chronic kidney disease.
  • the present invention provides ferric citrate for use in a method of preventing, reversing, maintaining or delaying progression of chronic kidney disease, comprising administering to said subject an effective amount of a ferric citrate compound that has a dissolution rate of at least 2 mg/cm 2 /min.
  • Representative ranges of the dissolution rate include, but are not limited to, from 2.5 mg/cm 2 /min to 3.0 mg/cm 2 /min., or from 3.0 mg/cm 2 /min to 3.5 mg/cm 2 /min., or from 3.5 mg/cm 2 /min to 4.0 mg/cm 2 /min.
  • the ferric citrate compound is obtainable by a method comprising the steps of: a) obtaining ferric chloride hexahydrate; b) adding sodium hydroxide to the ferric chloride hexahydrate under conditions suitable to produce a mixture comprising polyiron oxide; c) isolating a precipitate from the mixture; d) adding crystalline citric acid to the precipitate; e) heating crystalline citric acid and the precipitate thereby forming a ferric citrate solution; and f) precipitating ferric citrate from the ferric citrate solution by an organic solvent.
  • a subject is a human or an animal.
  • the subject may have any stage of chronic kidney disease (e.g. end stage renal disease), or is undergoing renal dialysis.
  • the ferric citrate compound may be administered orally or any other appropriate route generally known in the art and the ferric citrate compound can be formulated into a number of formats generally known in the art. Representative formats include a tablet, a powder, a suspension, an emulsion, a capsule, a lozenge, a granule, a troche, a pill, a liquid, a spirit, or a syrup.
  • treatment with the ferric citrate compound results in decreased serum creatinine and BUN level in the subject. In another embodiment, treatment with the ferric citrate compound results in decreased phosphorus and calcium and phosphorus product (CaxP) levels in serum.
  • CaxP calcium and phosphorus product
  • treatment with the ferric citrate compound would prevent, reverse, maintain, or delay progression of chronic kidney disease.
  • development of hyperparathyroidism, bone disorder, or cardiovascular disease in the subject is prevented, reversed, maintained or delayed.
  • calcium phosphate precipitation in the subject's renal tissue is prevented, reversed, maintained or delayed.
  • kidney stone formation is prevented, reversed, maintained or delayed.
  • development of metabolic acidosis in the subject is prevented, reversed, maintained or delayed.
  • the present invention also provides uses of a ferric citrate compound described herein for preparation of a medicament for treating a subject having chronic kidney disease.
  • the ferric citrate compound has a dissolution rate of at least 2 mg/cm 2 /min. In another embodiment, the ferric citrate compound has a dissolution rate from 2 to 4 mg/cm 2 /min. Ferric citrate compound may be administered at a dose of from 2 to 20 mg/day. Also, it is preferably administered orally.
  • the present invention also provides a therapeutic regimen for treating a subject having chronic kidney disease; the regiment comprises a pharmaceutical composition comprising an acceptable carrier and an effective amount of ferric citrate compound having a dissolution rate of at least 2 mg/cm 2 /min., wherein the pharmaceutical composition is administered in single or multiple doses regimens.
  • the present invention also provides a pharmaceutical composition for use in the manufacture of a medicament for preventing, reversing, maintaining or delaying progression of chronic kidney disease, wherein the composition comprises ferric citrate, and the ferric citrate is obtainable by a method comprising the steps of: a) obtaining a ferric chloride hexahydrate; b) adding sodium hydroxide to ferric chloride hexahydrate under conditions suitable to produce a mixture comprising polyiron oxide; c) isolating a precipitate from the mixture; d) adding crystalline citric acid to the precipitate; e) heating crystalline citric acid and the precipitate thereby forming a ferric citrate solution; and f) precipitating ferric citrate from the ferric citrate solution by an organic solvent.
  • Said composition comprises an effective amount of a ferric citrate compound having a dissolution rate of at least 2 mg/cm 2 /min.
  • the above pharmaceutical composition is in a form suitable for oral administration.
  • ferric citrate compounds of the present invention can be used to modify the progression of chronic kidney disease (CKD) in a subject; for example, the progression of CKD can be prevented, reversed, maintained, or delayed.
  • CKD chronic kidney disease
  • these ferric citrate compounds preferably have or include the following properties:
  • the present invention encompasses ferric citrate compounds for use in a method of preventing, reversing, maintaining, or delaying progression of chronic kidney disease, wherein the ferric citrate compounds possess certain characteristics as described herein.
  • ferric citrate compounds produced according to the methods described herein are useful in the treatment of hyperphosphatemia, metabolic acidosis, and any other disorders responsive to ferric citrate compound therapy. Because the ferric citrate compounds of the present invention are more soluble than commercially available ferric citrate compounds, smaller amounts of the ferric citrate compounds of the present invention can be used to effectively treat patients suffering from such disorders.
  • the ferric citrate of the present invention has a significantly higher rate of aqueous solubility under physiological conditions than commercially available forms of ferric citrate, and therefore the ferric citrate of the present invention is believed to provide a significant improvement in the orally effective use of ferric citrate at a reduced dosage.
  • the ferric citrate of the present invention will provide a lower incidence of ulcerative gastrointestinal adverse effects associated with commercially available ferric citrate compounds.
  • the increased rate of dissolution of the ferric citrate of the present invention will provide a more rapid onset of action in binding to dietary phosphate.
  • the ferric citrate compounds of the present invention are more soluble over a wider pH range than commercially available ferric citrate compounds; therefore, the ferric citrate compounds of the present invention can be more effective by being soluble in the small intestine.
  • the ferric citrate compounds of the present invention can be administered in a number of forms generally known in the art.
  • Pharmaceutical compositions comprising the ferric citrate compounds of the present invention include solids, liquids, or semi-solid forms, such as gels, syrups, chewables or pastes.
  • the ferric citrate compounds of the present invention can be administered alone or in combination with a pharmaceutically acceptable carrier.
  • Orally administrable forms include a tablet, a powder, a suspension, an emulsion, a capsule, a granule, a troche, a pill, a liquid, a spirit, or a syrup.
  • the composition can be administered to human beings or other animals suffering from illnesses responsive to ferric citrate compound therapy.
  • an effective amount of pharmaceutical-grade ferric citrate can be readily determined by one of ordinary skill in the art.
  • an effective dose may be from 2 to 100 grams per day, preferably between 2 and 60 grams per day.
  • a daily effective amount may be 2, 4, 6, or 8 grams.
  • compositions comprising pharmaceutical grade ferric citrate compounds of the present invention are suitable for treating hyperphosphatemia, or other disorders characterized by high serum phosphate levels. Therefore, the invention encompasses treating subjects or patients with various renal diseases; e.g., End Stage Renal Diseases (ESRD), Chronic Kidney Disease (CKD) or other relate kidney diseases, or subjects and patients who are on dialysis but not limited to hemodialysis.
  • ESRD End Stage Renal Diseases
  • CKD Chronic Kidney Disease
  • compositions comprising pharmaceutical grade ferric citrate compounds of the present invention, such as ferric citrate, may be used in a method of treating subjects or patients with metabolic acidosis.
  • Other disorders that may be ameliorated by the conversion of citrate to bicarbonate are also encompassed by the invention described.
  • the pharmaceutical composition according to the present invention may be used in a method of preventing, reversing, maintaining or delaying progression of chronic kidney disease in a a human or non-human subject or patient.
  • stage 1 is the least severe and stage 5 the most severe.
  • stage 5 the most severe.
  • dialysis is not required.
  • a patient may require dialysis treatment three times per week.
  • elevated phosphate levels are observed at all stages of chronic kidney disease. Therefore, an embodiment of the invention is a method of treating a subject or person with early or mid-stage chronic kidney disease, with a composition comprising pharmaceutical-grade ferric citrate in order to achieve a lower serum phosphate level.
  • the pharmaceutical composition may be used in a method of preventing, reversing, maintaining or delaying progression with late-stage chronic kidney disease in human or non-human subject or patient who is undergoing hemodialysis, by administering a composition comprising pharmaceutical-grade ferric citrate of the present invention. It is generally known that hemodialysis is not sufficiently effective in reducing serum phosphate level. The treatment of a subject or person with late stage kidney disease is applicable whether or not the subject or person is currently undergoing hemodialysis treatment.
  • the pharmaceutical composition may be used in a method of preventing, reversing, maintaining or delaying progression of chronic kidney disease in a subject or a patient undergoing peritoneal dialysis with the pharmaceutical-grade ferric citrate-containing compositions described herein. It is known that peritoneal dialysis is not sufficiently effective in reducing serum phosphate levels.
  • the subject is a human or an animal.
  • the subject may have end stage renal disease, or is undergoing renal dialysis.
  • an effective amount of a ferric citrate compound that has a dissolution rate of at least 2 mg/cm 2 /min is administered to said subject.
  • Representative ranges of the dissolution rate include from 2.5 mg/cm 2 /min to 3.0 mg/cm 2 /min., or from 3.0 mg/cm 2 /min to 3.5 mg/cm 2 /min., or from 3.5 mg/cm 2 /min to 4.0 mg/cm 2 /min.
  • the ferric citrate compound is prepared according a method comprising the steps of: (a)obtaining ferric chloride hexahydrate; b) adding sodium hydroxide to the ferric chloride hexahydrate under conditions suitable to produce a mixture comprising polyiron oxide; c) isolating a precipitate from the mixture; d) adding crystalline citric acid to the precipitate; e) heating crystalline citric acid and the precipitate thereby forming a ferric citrate solution; and f) precipitating ferric citrate from the ferric citrate solution by an organic solvent.
  • the sodium hydroxide is added at a rate of less than 20 ml/min, preferably between 10 ml/min to 20 ml/min., and the sodium hydroxide is added to the ferric chloride hexahydrate at a temperature of less than 40°C, preferably between about 10°C to about 40°C.
  • the citric acid and the precipitate are heated to a temperature of between 80°C to 90°C.
  • Precipitating the ferric citrate compound from the ferric citrate solution by an organic solvent comprises cooling the ferric citrate solution to less than 30°C before adding the organic solvent, preferably the ferric citrate acid solution is cooled to a temperature between 10°C to 30°C.
  • Citric acid is used in the method of synthesizing the ferric citrate compound.
  • the citric acid is in crystalline form.
  • a number of organic solvent such as ethanol, methanol, butanol, isopropyl alcohol, acetone, and tetrahydrofuran can be used in synthesizing the ferric citrate compound described herein.
  • the ferric citrate compound can be administered at an effective dose determined by one of ordinary skill in the art, ranging from 2 gm/day to 20 gm/day.
  • the ferric citrate compound can be administered orally or any other appropriate route readily determined by one of ordinary skill in the art.
  • the ferric citrate compound can be formulated as a tablet, a powder, a suspension, an emulsion, a capsule, a lozenge, a granule, a troche, a pill, a liquid, a spirit, or a syrup.
  • treatment with the ferric citrate compound results in decreased serum creatinine and BUN level in the subject. In another embodiment, treatment with the ferric citrate compound results in decreased phosphorus, calcium, and phosphorus product (CaxP) levels in serum.
  • CaxP phosphorus product
  • ferric citrate compound and pharmaceutical composition may thus be used in a method of preventing, reversing, maintaining, or delaying progression of chronic kidney disease.
  • development of hyperparathyroidism, bone disorder, or cardiovascular disease in the subject is prevented, reversed, maintained or delayed.
  • calcium phosphate precipitation in the subject's renal tissue is prevented, reversed, maintained or delayed.
  • kidney stone formation is prevented, reversed, maintained or delayed.
  • development of metabolic acidosis in the subject is prevented, reversed, maintained or delayed.
  • the present invention thus provides ferric citrate for use in a method of preventing, reversing, maintaining or delaying progression of chronic kidney disease, comprising administering to said subject an effective amount of a ferric citrate compound, wherein the ferric citrate compound is prepared according a method comprising the steps of: (a)obtaining ferric chloride hexahydrate; b) adding sodium hydroxide to the ferric chloride hexahydrate under conditions suitable to produce a mixture comprising polyiron oxide; c) isolating a precipitate from the mixture; d) adding crystalline citric acid to the precipitate; e) heating crystalline citric acid and the precipitate thereby forming a ferric citrate solution; and f) precipitating ferric citrate from the ferric citrate solution by an organic solvent.
  • ferric citrate that has enhanced dissolution rate (e.g. a dissolution rate of at least 2 mg/cm 2 /min.), thereby producing therapeutic effects described above.
  • Ferric citrate may have a dissolution rate ranging from 2 to 4 mg/cm 2 /min.
  • ferric citrate is administered at a dose of from 2 to 20 gm/day.
  • Ferric citrate may be preferably administered orally.
  • the present invention also provides a pharmaceutical composition for use in a method of preventing, reversing, maintaining or delaying progression of chronic kidney disease, wherein the composition comprises ferric citrate, and the ferric citrate is obtainable by a method comprising the steps of: a) obtaining a ferric chloride hexahydrate; b) adding sodium hydroxide to ferric chloride hexahydrate under conditions suitable to produce a mixture comprising polyiron oxide; c) isolating a precipitate from the mixture; d) adding crystalline citric acid to the precipitate; e) heating crystalline citric acid and the precipitate thereby forming a ferric citrate solution; and f) precipitating ferric citrate from the ferric citrate solution by an organic solvent:
  • the subject is a human or an animal.
  • the subject may have end stage renal disease, or is undergoing renal dialysis.
  • the pharmaceutical composition comprises ferric citrate compound having a dissolution rate of at least 2 mg/cm 2 /min.
  • the dissolution rate is from 2 mg/cm 2 /min to 4 mg/cm 2 /min.
  • the composition is in a form suitable for oral administration, e.g. as a tablet, a powder, a suspension, an emulsion, a capsule, a lozenge, a granule, a troche, a pill, a liquid, a spirit, or a syrup.
  • Such dissolution rate may be from 2 to 4 mg/cm 2 /min.
  • the present invention also provides a therapeutic regimen for treating a subject having chronic kidney disease, the regiment comprises a pharmaceutical composition comprising an acceptable carrier and an effective amount of ferric citrate compound having a dissolution rate of at least 2 mg/cm 2 /min., wherein the pharmaceutical composition is administered in single or multiple doses regimens.
  • ferric citrate having a dissolution rate of at least 2 mg/cm 2 /min. would be useful in the present method.
  • the dissolution rate of the ferric citrate compound can be from 2.5 mg/cm 2 /min to 3.0 mg/cm 2 /min., or from 3.0 mg/cm 2 /min to 3.5 mg/cm 2 /min., or from 3.5 mg/cm 2 /min to 4.0 mg/cm 2 /min.
  • at least a portion of the pharmaceutical composition is administered orally.
  • the subject is having end stage renal disease, and the method may optionally comprise renal dialysis or peritoneal dialysis.
  • the present invention also provides an orally administrable form of ferric citrate for preventing, reversing, maintaining or delaying progression of chronic kidney disease
  • the orally administrable form is prepared from a pharmaceutical composition comprising a form of a ferric citrate obtainable by the method comprising the steps of: a) obtaining a ferric chloride hexahydrate; b) adding sodium hydroxide to ferric chloride hexahydrate under conditions suitable to produce a mixture comprising polyiron oxide; c) isolating a precipitate from the mixture; d) adding crystalline citric acid to the precipitate; e) heating crystalline citric acid and the precipitate thereby forming a ferric citrate solution; and f) precipitating ferric citrate from the ferric citrate solution by an organic solvent.
  • Said ferric citrate has a dissolution rate of at least 2 mg/cm 2 /min.
  • the dissolution rate is from 2 mg/cm 2 /min to 4 mg/cm 2 /min.
  • said orally administrable form may be tablet, a powder, a suspension, an emulsion, a capsule, a lozenge, a granule, a troche, a pill, a liquid, a spirit, or a syrup.
  • the present invention also provides a use of the above pharmaceutical composition in preparation of a medicament for treating a subject having chronic kidney disease.
  • the subject is having end stage renal disease or undergoing renal dialysis.
  • the flowchart 10 is a general process for synthesizing a form of ferric citrate compound which can be used in the present invention.
  • the starting materials as indicated in box 20, comprise soluble ferric iron salts.
  • the soluble ferric iron salts can comprise ferric chloride hexahydrate (FeCl 3 6H 2 O), as indicated in box 21, or any other suitable soluble ferric iron salt.
  • an alkaline metal hydroxide (box 30) is added at a specific rate and temperature to the soluble ferric iron salt.
  • the alkaline metal hydroxide can comprise sodium hydroxide, potassium hydroxide, or any other suitable alkaline metal hydroxide as indicated in box 31.
  • the colloidal suspension precipitate is collected and rinsed (box 40) with distilled water to remove any soluble impurities. After rinsing, the precipitate is re-suspended and, as indicated in box 50, crystalline citric acid is added to the precipitate and heated to a particular temperature range, preferably between 80°C to 90°C. The addition of citric acid allows the acid to form soluble complexes with the precipitate.
  • the ferric citrate compound is precipitated out of solution with an organic solvent to form a novel form of ferric citrate compound (box 70).
  • organic solvents can be used, including, but not limited to, the solvents described in box 61, such as ethanol, methanol, butanol, acetone, isopropyl alcohol, tetrahydrofuran, or any other suitable organic solvent.
  • the starting materials for making a ferric citrate comprise a 1.85M solution of ferric chloride hexahydrate (FeCl 3 6H 2 O).
  • a volume of 5M sodium hydroxide necessary to produce a 1:3 ratio of ferric iron to hydroxide ion is added to the ferric chloride hexahydrate solution at a rate of less than 20 ml per minute, preferably between 10 ml per minute and 20 ml per minute.
  • the temperature of the mixture is maintained below 40°C, preferably between 10°C and 40°C, while the sodium hydroxide is added to form a polyiron oxide colloidal suspension of ferric hydroxide.
  • the pH of the suspension is measured while the sodium hydroxide is added.
  • the suspension is cooled until it is less than 30°C, preferably between about 10°C to about 30°C.
  • the suspension is then filtered through a 1 mm pore filter to breakup aggregates and large particles of ferric hydroxide precipitate are then removed.
  • the filtered ferric hydroxide suspension is then centrifuged. The supernatant is discarded, and the precipitated ferric hydroxide is centrifuged again to remove any remaining supernatant.
  • the ferric hydroxide precipitate is then resuspended with distilled water. The centrifugation-resuspension steps are repeated two more times to wash the ferric hydroxide precipitate and remove water soluble impurities.
  • the resulting ferric hydroxide precipitate is then homogenized.
  • An amount of citric acid necessary to produce a 1:1 ratio of ferric iron to citrate is added to the precipitate.
  • the mixture is heated to between 80°C to 90°C in an oil bath until the color of the mixture changes from orange-brown to a clear black-brown, or until all of the ferric hydroxide precipitate is dissolved.
  • the reaction is cooled until it is less than 30°C, preferably between 10°C to 30°C, and the pH is measured to determine that it is within 0.8 and 1.5.
  • the reaction is centrifuged, and the supernatant is collected.
  • Ferric citrate is precipitated from the supernatant by adding 5 volumes of organic solvent.
  • Various organic solvents can be used, including ethanol, methanol, butanol, acetone, isopropyl alcohol, or tetrahydrofuran.
  • the solvent is added, the mixture is stirred until a light beige precipitate forms.
  • the suspension is centrifuged and the supernatant is discarded.
  • the precipitate is washed and centrifuged with the solvent two more times.
  • the precipitate is then dried in a vacuum oven for 8 to 16 hours at ambient temperature or by any other suitable industrial processes such as fluidized-bed drying.
  • the dried precipitate is ground with a mortar and pestle and dried for another 8 to 24 hours at ambient temperature.
  • the fine precipitate is finely ground by milling again and screened through a 45 mesh size (35 micron) sieve.
  • the novel form of ferric citrate powder is dried in the vacuum oven again or fluidized-bed drying again and dried at ambient temperature until 1 hour of drying leads to less than 0.25% loss in weight.
  • ferric citrate compounds produced according to the methods described above are more soluble than commercially available ferric citrate compounds, over a wider range of pH levels. This increase in solubility of the ferric citrate compounds of the present invention is believed to be a result of the unique significantly large active surface area of the ferric citrate compounds of the present invention. For example, at pH 8.0, the intrinsic dissolution rate of ferric citrate of the present invention is 3.32 times greater than the commercially available ferric citrate. See Table 1.
  • the intrinsic dissolution rates of commercially available ferric citrate were compared with the ferric citrate of the present invention.
  • the intrinsic dissolution rate is defined as the dissolution rate of pure substances under the condition of constant surface area.
  • the dissolution rate and bioavailability of a drug substance is influence by its solid state properties: crystallinity, amorphism, polymorphism, hydration, solvation, particle size and particle surface area.
  • the measured intrinsic dissolution rate is dependent on these solid-state properties and is typically determined by exposing a constant surface area of a material to an appropriate dissolution medium while maintaining constant temperature, stirring rate, and pH.
  • the intrinsic dissolution rates are presented in Table 1.
  • Intrinsic Dissolution Rates of Ferric Citrate at 37°C in Solutions of pH 8 Sample Rate of Acetone Addition (ml/min) Intrinsic Dissolution Rates (mg/cm2/min) Mean Intrinsic Dissolution Rates (mg/cm2/min) RFS-12 (sigma / commercially available) 10.0 0.83 0.83 STM-134 (reference material) 10.0 1.88 1.88 PAN031203A (experimental batch 1) 10.0 3.82 3.32 PAN031203B (experimental batch 2) 10.0 4.00 PAN031203C (experimental batch 3) 9.5 2.68 PAN031203D (experimental batch 4) 40 2.95 PAN031203E (experimental batch 5) 4.4 3.13
  • the BET active surface area of the ferric citrate of the present invention is at least 16 times larger than the commercially available ferric citrate. See Table 2.
  • active surface area is based on BET theory which describes the phenomenon of mass and energy interaction and phase changes during gas adsorption onto solid surfaces and in pore spaces.
  • BET active surface area measurement the volume of a monolayer of gas is determined which allows the surface area of the sample to be determined using the area occupied by a single layer of adsorbed gas molecule.
  • Table 2 is a comparison of the active surface area of the ferric citrate of the present invention compared to the active surface area of commercially available ferric citrate compounds.
  • Ferric citrate is supplied in 500 mg capsules, whereas the placebo will be provided in identical-looking capsules (indistinguishable from those containing the active drug); the placebo capsules will contain sorbitol and colorant to match the powder color of the active capsules.
  • the placebo capsule shells will be identical to the active capsule shells.
  • study drug supplies must be stored under secure conditions and are not to be used after their expiration date, which is imprinted on the study drug container.
  • the study drugs should be kept under controlled conditions (15 to 30°C; 59 to 86°F) in a tightly closed container, protected from light.
  • ferric citrate (3 g daily) to calcium carbonate (3g daily) for reducing serum P0 4 in patients with End Stage Renal Disease (ESRD). This dose of ferric citrate was associated with mild, but tolerable GI symptoms.
  • ferric citrate chosen for study or treatment may be from 1 to 30 grams of ferric citrate per day. In part, this may depend on the nature of the formulation provided. For example, ferric citrate capsules may be administered up to a daily dose of 15 grams/day, whereas the tablet form may be administered up to 30 grams/day. Thus, there is a very broad range of dosing regimens encompassed by the invention.
  • the term "subject” refers to either a human or non-human animal.
  • the optimal dosage of an individual subject or groups may be determined as follows. A dose of one or two grams per day is merely suggested as an illustrative starting dose. The daily dose may be increased as needed until the desired result is observed.
  • the intent of the invention is to not limit the dose range employed. Therefore, depending on the subject(s) the daily dose administered may be thirty, forty, fifty, sixty, seventy, eighty, ninety or one hundred grams per day.
  • the safety profile of the pharmaceutical-grade ferric citrate allows the implementation of a broad range of doses.
  • a non-limiting example of a dosing regimen is provided below. This is not meant to limit the invention as to how an effective amount of ferric citrate is selected, or the form in which it is provided or the frequency of administering the composition per day.
  • the following merely illustrates how ferric citrate and placebo may be administered; e.g., as 500 mg capsules of identical appearance. All patients may receive (in a blinded fashion) 4 capsules with each of three meals, on a daily basis, for 28 days. Patients will be instructed to take the study medication within 10 minutes of finishing their meals (breakfast, lunch, and dinner).
  • the number of placebo, and active capsules to be taken at each meal are as follows:
  • Each patient's participation in the trial lasts for up to 8 weeks: the screening period (approximately 1-2 weeks), a 1-2 week washout, and 4 weeks of treatment with study medication.
  • GloboMax will be the primary data management, monitoring, and coordinating center. Case report forms (CRF) will be provided for each subject. Subjects will not be identified by name or initials on CRFs. The CRF will be monitored at the clinical sites and collected by GloboMax's study monitor. Audited CRFs will be used to create electronic data files.
  • CRF Case report forms
  • endpoints reflect biochemical and clinical issues being addressed at the outset. Additional clinical and biochemical issues are addressed as they arise. Therefore, the endpoints are not meant to limit the totality of relevant findings and measurements collected in these, or future studies.
  • Study Design Randomized, double-blind, placebo-controlled, dose-ranging study to assess the effect of ferric citrate on serum phosphate concentrations in patients with ESRD on hemodialysis. Patients are assessed at Study Days 14 and 28 for effectiveness as measured by serum phosphate concentrations. Patients who received one or more doses of study medication are also assessed for safety.
  • Study Duration 8 weeks (including the screening period, 2 weeks washout, 4 weeks treatment)
  • Results show a decrease in serum PO4 and Ca*PO4 at 0, 2, 4 and 6 gm/day (given as TID immediately after meals, i.e., within 10 minutes). Ferric citrate is administered orally, and is given equally three times a day.
  • treatments using pharmaceutical-grade ferric citrate provide several advantages over chemical grade ferric citrate.
  • pharmaceutical-grade ferric citrate demonstrates an efficacy approximately equal to that of chemical grade ferric citrate, it achieves this result with less adverse side effects than chemical grade ferric citrate.
  • Figure 2 also indicates that adverse side effects associated with administering pharmaceutical-grade ferric citrate were not statistically different from those associated with the placebo.
  • An advantage of this safety profile is that an individual patient may have his dosing of pharmaceutical-grade ferric citrate titrated over a broad range of doses with less concern about side effect. In this way, a patient's individual treatment may be tailored to suit his specific needs and tolerances.
  • Glomerular filtration rate (GFR) level correlates with structural kidney damage and is used as a golden standard to measure kidney function.
  • GFR can be estimated by the biomarkers serum creatinine. As renal function deteriorates, kidney lost its function to excrete creatinine effectively and lead to creatinine retention in the body. Therefore, increase of serum creatinine indicates lowering GFR and is an important sign of kidney deterioration.

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